Adenomatous polyposis coli mutants dominantly activate Hsf1- dependent cell stress pathways through inhibition of microtubule dynamics

Alexander E. Davies, Kaitlyn Kortright, Kenneth B. Kaplan

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Cancer cells up-regulate cell stress pathways, including the protein chaperone Hsp90. Increases in Hsp90 are believed "buffer" mutant protein activities necessary for cancer phenotypes. Activation of the cell stress pathway also alters the transcriptional landscape of cells in ways that are critical for cancer progression. However, it is unclear when and how the cell stress pathway is de-regulated during cancer progression. Here we report that mutations in adenomatous polyposis coli (APC) found in colorectal cancer activate cell stress pathways in mouse intestinal crypt cells, prior to loss of heterozygosity at APC or to the appearance of canonical intestinal cancer markers. Hsp90 levels are elevated in normal APC heterozygote crypt cells and further elevated in non-cancer cells adjacent to dysplasias, suggesting that the Hsp90 stress pathway marks the "cancer-field" effect. Expression of mutant APC in normal human epithelial cells is sufficient to activate a cell stress pathway via perturbations in microtubule dynamics. Inhibition of microtubule dynamics is sufficient to activate an Hsf1-dependent increase in gene transcription and protein levels. We suggest that the early activation of this Hsf1 dependent cell stress pathway by mono-allelic mutations in APC can affect cell programming in a way that contributes to cancer onset.

Original languageEnglish (US)
Pages (from-to)25202-25216
Number of pages15
JournalOncotarget
Volume6
Issue number28
DOIs
StatePublished - 2015

Fingerprint

Adenomatous Polyposis Coli
Microtubules
Neoplasms
Intestinal Neoplasms
Mutation
Loss of Heterozygosity
Mutant Proteins
Heterozygote
Colorectal Neoplasms
Buffers
Proteins
Up-Regulation
Epithelial Cells

Keywords

  • Adenomatous polyposis coli
  • Cancer field effect
  • Cell stress
  • Hsp90
  • Microtubules

ASJC Scopus subject areas

  • Oncology

Cite this

Adenomatous polyposis coli mutants dominantly activate Hsf1- dependent cell stress pathways through inhibition of microtubule dynamics. / Davies, Alexander E.; Kortright, Kaitlyn; Kaplan, Kenneth B.

In: Oncotarget, Vol. 6, No. 28, 2015, p. 25202-25216.

Research output: Contribution to journalArticle

Davies, Alexander E. ; Kortright, Kaitlyn ; Kaplan, Kenneth B. / Adenomatous polyposis coli mutants dominantly activate Hsf1- dependent cell stress pathways through inhibition of microtubule dynamics. In: Oncotarget. 2015 ; Vol. 6, No. 28. pp. 25202-25216.
@article{bf41abcd8445440fb92f80cfce898312,
title = "Adenomatous polyposis coli mutants dominantly activate Hsf1- dependent cell stress pathways through inhibition of microtubule dynamics",
abstract = "Cancer cells up-regulate cell stress pathways, including the protein chaperone Hsp90. Increases in Hsp90 are believed {"}buffer{"} mutant protein activities necessary for cancer phenotypes. Activation of the cell stress pathway also alters the transcriptional landscape of cells in ways that are critical for cancer progression. However, it is unclear when and how the cell stress pathway is de-regulated during cancer progression. Here we report that mutations in adenomatous polyposis coli (APC) found in colorectal cancer activate cell stress pathways in mouse intestinal crypt cells, prior to loss of heterozygosity at APC or to the appearance of canonical intestinal cancer markers. Hsp90 levels are elevated in normal APC heterozygote crypt cells and further elevated in non-cancer cells adjacent to dysplasias, suggesting that the Hsp90 stress pathway marks the {"}cancer-field{"} effect. Expression of mutant APC in normal human epithelial cells is sufficient to activate a cell stress pathway via perturbations in microtubule dynamics. Inhibition of microtubule dynamics is sufficient to activate an Hsf1-dependent increase in gene transcription and protein levels. We suggest that the early activation of this Hsf1 dependent cell stress pathway by mono-allelic mutations in APC can affect cell programming in a way that contributes to cancer onset.",
keywords = "Adenomatous polyposis coli, Cancer field effect, Cell stress, Hsp90, Microtubules",
author = "Davies, {Alexander E.} and Kaitlyn Kortright and Kaplan, {Kenneth B.}",
year = "2015",
doi = "10.18632/oncotarget.4513",
language = "English (US)",
volume = "6",
pages = "25202--25216",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "28",

}

TY - JOUR

T1 - Adenomatous polyposis coli mutants dominantly activate Hsf1- dependent cell stress pathways through inhibition of microtubule dynamics

AU - Davies, Alexander E.

AU - Kortright, Kaitlyn

AU - Kaplan, Kenneth B.

PY - 2015

Y1 - 2015

N2 - Cancer cells up-regulate cell stress pathways, including the protein chaperone Hsp90. Increases in Hsp90 are believed "buffer" mutant protein activities necessary for cancer phenotypes. Activation of the cell stress pathway also alters the transcriptional landscape of cells in ways that are critical for cancer progression. However, it is unclear when and how the cell stress pathway is de-regulated during cancer progression. Here we report that mutations in adenomatous polyposis coli (APC) found in colorectal cancer activate cell stress pathways in mouse intestinal crypt cells, prior to loss of heterozygosity at APC or to the appearance of canonical intestinal cancer markers. Hsp90 levels are elevated in normal APC heterozygote crypt cells and further elevated in non-cancer cells adjacent to dysplasias, suggesting that the Hsp90 stress pathway marks the "cancer-field" effect. Expression of mutant APC in normal human epithelial cells is sufficient to activate a cell stress pathway via perturbations in microtubule dynamics. Inhibition of microtubule dynamics is sufficient to activate an Hsf1-dependent increase in gene transcription and protein levels. We suggest that the early activation of this Hsf1 dependent cell stress pathway by mono-allelic mutations in APC can affect cell programming in a way that contributes to cancer onset.

AB - Cancer cells up-regulate cell stress pathways, including the protein chaperone Hsp90. Increases in Hsp90 are believed "buffer" mutant protein activities necessary for cancer phenotypes. Activation of the cell stress pathway also alters the transcriptional landscape of cells in ways that are critical for cancer progression. However, it is unclear when and how the cell stress pathway is de-regulated during cancer progression. Here we report that mutations in adenomatous polyposis coli (APC) found in colorectal cancer activate cell stress pathways in mouse intestinal crypt cells, prior to loss of heterozygosity at APC or to the appearance of canonical intestinal cancer markers. Hsp90 levels are elevated in normal APC heterozygote crypt cells and further elevated in non-cancer cells adjacent to dysplasias, suggesting that the Hsp90 stress pathway marks the "cancer-field" effect. Expression of mutant APC in normal human epithelial cells is sufficient to activate a cell stress pathway via perturbations in microtubule dynamics. Inhibition of microtubule dynamics is sufficient to activate an Hsf1-dependent increase in gene transcription and protein levels. We suggest that the early activation of this Hsf1 dependent cell stress pathway by mono-allelic mutations in APC can affect cell programming in a way that contributes to cancer onset.

KW - Adenomatous polyposis coli

KW - Cancer field effect

KW - Cell stress

KW - Hsp90

KW - Microtubules

UR - http://www.scopus.com/inward/record.url?scp=84944463534&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84944463534&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.4513

DO - 10.18632/oncotarget.4513

M3 - Article

AN - SCOPUS:84944463534

VL - 6

SP - 25202

EP - 25216

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 28

ER -